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Vitamins


VITAMINS AND COFACTORS

Vitamins
? a group of organic compounds needed in small quantities in the diet for normal activity of tissues ? between 14 – 20 substances have been id

entified as vitamins ? many vitamins act as cofactors, coenzymes or prosthetic groups for enzymes ? most vitamins are derived from diet ? no calories are derived from vitamins

Vitamins
? first vitamin to be discovered was thiamine or vitamin B1 ? the term vitamin is derived from the fact that the substances are needed for life (vita) and because thiamine happened to be an amine; the term was coined as such ? however, not all vitamins are amines or nitrogen containing compounds ? vitamin requirements are usually expressed as RDA’s (Recommended Dietary Allowances) ? guidelines are provided by 2 organizations:
? the Food and Nutrition Board of the National Academy of SciencesNational Research Council ? the Food and Drug Administration (FDA)

RDAs
? Applications of RDAs include:
? evaluating the adequacy of the national food supply ? establishing standards for menu planning ? establishing nutritional policy for public institutions/organizations and hospitals ? evaluating diets in food consumption studies ? establishing labeling regulations ? setting guidelines for food product formulation ? developing materials for nutritional education

? RDAs have limitations:
? ? ? ? ? ? they are too complex for direct consumer use they do not state ideal or optimal levels of intake the allowances for some categories are based on limited data the data on some nutrients in foods is limited they do not evaluate nutritional status they do not apply to seriously ill or malnourished patients

Vitamin deficiencies
? primary food deficiency
? crop failure ? food storage loss ? food preparation loss

? increased requirements
? ? ? ? rapid growth increased physical activity pregnancy hyperthyroidism

? diminished food intake
? poverty ? anorexia ? chronic diseases

? increased loss
? drug therapy ? diuresis ? lactation

? diminished absorption
? absorption defect ? parasites ? malignancies

Vitamin loss
Loss is seen mainly in storage or food preparation

? Vitamin A: sensitive to oxygen and light ? Vitamin D: usually little loss ? Vitamin E: sensitive to oxidation especially when heated or with alkali ? Vitamin K: sensitive to acids, alkali, light and oxidizing agents ? Vitamin C: very sensitive to oxidation, especially when heated in contact with metals ? Vitamin B complex: water solubility results in loss in cooking water ? Riboflavin is sensitive to light

Vitamins
? Vitamins are typically divided into 2 groups:
– The fat soluble vitamins ? A, D, E, and K – The water soluble vitamins
? The B vitamins (B1, B2, B3, B6, B7, B12 and pantothenic acid) ? Ascorbic acid (vitamin C)

Cofactors
? provide “chemical teeth” for enzymes ? sometimes referred to as coenzymes ? enzymes: proteins with catalytic activity
– simple enzymes: large protein (polypeptide) that catalyzes a reaction. The enzyme gets all the “tools” (chemical teeth) it needs from the amino acids. However, there are only 20 different amino acids – conjugated enzymes : apoenzyme + cofactor = holoenzyme

Example of a simple enzyme
Usually electron-rich side chains are involved in the catalysis
CH2OH H N

CH2 N

Aliphatic chains are normally involved in hydrophobic interactions
all these tools come from amino acids in the protein active site

CH2-COOH

A serine protease enzyme such as chymotrypsin

Example of a conjugated enzyme
cofactor needed for reaction

Zinc protease such as ACE

H N

Zn+2 OH

O

R' N N

R

H

O

PRODUCTS + ENZYME

Water soluble vitamins

Thiamine or Vit. B1
NH2 S CH2 N N CH2-CH2-OH H3C N H3C

THIAMINE

Vitamin B1; antiberi-beri vitamin; antineuritic factor was the first water soluble vitamin discovered (Eijkman)

Thiamine
? has the odor and flavor of yeast ? slowly destroyed by moist heat; more rapidly destroyed in a basic medium than in an acid one ? source: whole cereals and grains; yeast; organ meat ? pharmaceutical products use the hydrochloride or mononitrate salts ? active form is thiamine pyrophosphate (formed by the action of thiamine diphosphotransferase) ? involved in the oxidative decarboxylation of pyruvic acid and α-ketoglutaric acid ? involved in the transketolase reactions of the triose phosphate pathway ? also required for nerve function (unrelated to coenzyme activity)

Thiamine pyrophosphate
? the key portion of this cofactor is the thiazolium ring with its acidic hydrogen ? the hydrogen is removed by the enzyme forming an ylid (anion next to cation) ? the anion can then react with carbonyl groups in such molecules as pyruvate ? the pyrophosphate functionality acts as a chemical handle which holds the cofactor in place within the enzyme

Conversion of thiamine to TPP

Thiamine deficiency
? earliest symptoms of thiamine deficiency include:
– – – – – – constipation appetite suppression nausea mental depression peripheral neuropathy fatigue

? beri-beri (once associated with white polished rice diets and with highly milled wheat diets) ? 2 clinical types
? dry beri beri or neuritic beriberi – associated with polyneuropathy (depressed peripheral nerve function, sensory disturbance, loss of reflexes and motor control and muscle wasting ? wet beri beri or cardiovacular beriberi – edema, congestive heart failure

Riboflavin or Vitamine B2
? vitamin B2, lactoflavin (ovo, hepato, verdo), vitamin G ? a heterocyclic flavin linked to ribose analogous to the nucleosides in RNA ? orange-yellow fluorescent compound ? found in significant quantities in green leafy vegetables, milk and meats ? heat stable, but easily destroyed by light ? recommended intake is related to energy intake (kcal) – RDA 1 – 2 mg/day

H 2C H H H H H 3C C C C C N

OH OH OH OH H N

Vitamine B2 or Riboflavin (dimethylisoalloxazine) ring system – confers some degree of planarity to the molecule and also color (yellow)

O N

H 3C

N O RIBOFLAVIN

H

Riboflavin
? involved in 2 cofactors:
– riboflavin phosphate (flavin mononucleotide, FMN) – flavin adenine dinucleotide (FAD)

? involved in the metabolism of carbohydrates, fats and proteins (flavin dehydrogenases/flavopr oteins) ? hydrogen carriers in the respiratory chain

Riboflavin
H H3C N N N H3C N O FAD (oxidized form) hydrogen addition occurs in 2 steps H O H3C N N N H3C N H O H O

FADH (reduced form) 2

Fatty acyl-CoA desaturase
H H R SCoA FAD FADH 2 H O fatty acyl-CoA desaturase O H R H SCoA

Important step in the biosynthesis of unsaturated fats; this reaction is actually more complex than shown here and involves other cofactors, but FAD is a key cofactor for the enzyme

Riboflavin deficiency
? seldom seen in industrialized societies ? deficiency when seen:
? ? ? ? ? ? ? cheilosis (vertical fissure in the lips) angular stomatitis (craks in the corner of the mouth) glossitis photophobia seborrheic dermatitis normochromic normocytic anemia usually encountered along with pellagra (niacin deficiency) ? newborns treated for hyperbilirubinemia by phototherapy (riboflavin is unstable to light)

Pyridoxine (vitamin B6)
CH2OH HO CH2OH

H3C

N PYRIDOXINE

A pyridine derivative

Other forms of B-6
CHO HO CH2OH HO CH 2NH 2 CH2OH

H 3C

N

H 3C

N

D PYRIXOXAL

PYRIDOXAMINE

Collectively, pyridoxine, pyridoxal and pyridoxamine are known as vitamin B6

Pyridoxine
? vitamin B6, rat “acrodynia factor”, antidermatitis factor ? widespread occurrence
? pyridoxine: mostly in vegetable products ? pyridoxal and pyridoxamine: mostly in animal products

? pyridoxine is stable in acid solution, but unstable in neutral or alkaline solutions (destroyed by light)

Pyridoxal phosphate
? pyridoxine is converted to pyridoxal phophate by phosphorylation and oxidation to the aldehyde ? pyridoxal phosphate is then attached to the holoenzyme via a covalent bond to a lysine residue (a Schiff’s base) ? the Schiff’s base bond is readily broken and reformed ? this reversibility is very important in the biochemical action of this cofactor
H O N

O CH2OH CH2OH HO

H

HO

CH2OPO3 HN

H
CH2OPO3

H3C

N H

H3C

N H

HO

pyridoxine

pyridoxal phosphate

H3C

N H

Pyridoxal phosphate
Biochemical functions:
1. 2. 3. 4. 5. 6. 7. Decarboxylation of amino acids Transaminase reactions Racemization reactions Aldol cleavage reactions Transulfuration reactions Conversion of tryptophan to niacin Conversion of linoleic acid into arachidonic acid (prostaglandin precursor) 8. Formation of sphingolipids

Pyridoxine
? deficiency:
– difficult to produce in humans – may be accomplished artificially with a pyridoxine antagonist (deoxypyridoxine) – symptoms include: nausea and vomiting, seborrheic dermatitis, depression and confusion, mucous membrane lesions, peripheral neuritis, anemia

? can be monitored by measuring the level of xanthurenic acid in the urine ? this is related to a decrease in kynureninase activity (pyridoxal phosphate is the coenzyme) ? kynurenine, a breakdown product of tryptophan, is normally converted to kynurenic acid – but in B6 deficiency it is shunted to form xanthurenic acid

Pyridoxine can antagonize the antiparkinsonian use of L-DOPA
Brain

L-DOPA

L-DOPA

L-dopamine

B 6 stimulates this reaction outside of the brain CO
2

L-dopamine

use carbidopa: an inhibitor of DOPA decarboxylase in combination with DOPA: Sinemet 10/100 or Sinemet 25/250

Pyridoxine
? requirements:
? children: 0.5 – 1.2 mg ? adults: 2.0 mg ? pregnancy: 2.5 mg

– Requirement for B6 is proportional to the level of protein consumption

? therapeutic uses:
? ? ? ? deficiency to counterract the effects of antagonists certain rare forms of anemia in women taking oral contraceptives (estrogen shifts tryptophan metabolism

Ascorbic acid or Vitamin C
? vitamin C; anti-scorbutic vitamin (scurvy) ? structure is reminiscent of glucose ? produced in plants from glucose via the uronic pathway ? the enzyme gluconolactone oxidase converts gluconolactone to ascorbic acid ? exists in the enolic and ketonic forms ? sources: citrus fruits, tomatoes, green peppers, strawberries, cantaloupe, cabbage, turnips, peas, lettuce and asparagus

ASCORBIC ACID AND DEHYDROASCOBIC ACID

O HO O HO CH CH 2OH OH O O

O

O

CH CH 2OH OH

Ascorbic acid
? Biochemical functions:
– Production and maintenance of collagen
? Proline --------hydroxyproline ? Lysine -------- hydroxylysine

– Mitochondrial electron-transport chain (cytochrome C) – Metabolism of tyrosine
? Tyrosine ----- p-hydroxyphenylpyruvic acid---- 2,5dihydroxyphenylacetic acid (homogentisic acid)

Anti-oxidant properties of vitamin C:
helps preventing damage to cellular proteins and DNA
O HO OH O

O
HO O O OH

HO OH

O O

Normal metabolic processes in the cell lead to the generation of reactive oxidizing agents such as superoxide Superoxide can react with and damage protein and DNA, leading to cellular changes that can lead to premature aging and cancer Vitamin C reacts with superoxide, thus preventing this damage

Ascorbic acid
– conversion of folic acid to THFA – hydroxylation reactions of cholesterol to cholic acid – hydroxylation of tryptophan to 5hydroxytryptophan – regulation of cholesterol biosynthesis in the adrenal gland – aids in the absorption and utilization of iron – antioxidant properties may inhibit formation of nitrosamines during digestion of protein

Ascorbic acid
? defiency: scurvy
– hemorrhage from mucous membranes, mouth and GIT, skin and muscles – gingivitis: swelling, tenderness, redness and ulceration of gums – loosening or loss of teeth – swelling of joints – rarefaction of bones and dentine

Ascorbic acid
? requirements:
? children: 30 mg ? adults: 40 –80 mg ? pregnancy: 100 mg

? therapeutic uses
? scurvy ? idiopathic methemoglobinemia

? questionable use: common cold

Vitamin B12

Vitamin B12
? synthesized by bacteria only ? red in color, levorotatory and stable to heat ? commercially available either as cyano or hydroxocobalamin ? stored in the liver as the coenzyme ? absorbed only in the presence of the intrinsic factor (a glycoprotein released by parietal cells) ? transported to tissues via transcobalamin II ? present in foods such as liver, fish, eggs, milk ? absent in vegetables and fruits

Vitamin B12
? by far the most complex vitamin in structure ? made up of a planar corrin ring (4 pyrroles) ? the only vitamin that possesses a metal ion (cobalt) as part of its structure ? the major cofactor form of B12 is adenosylcobalamin or 5’deoxyadenosylcobalamin ? small amounts of methylcobalamin also occur (intermediate in methyl transfer reactions) ? the corrin ring is similar to the porphyrin ring system found in hemoglobin except that in corrin 2 of the pyrroles are linked directly (without methylene bridges) ? the cobalt is coordinated to the 4 pyrrole nitrogens ? one of the axial cobalt ligands is a nitrogen of the dimethylbenzimidazole group ? the other axial ligand may be CN, OH, CH3 or the 5’-carbon of a 5’-deoxyadenosyl group

H 2 NCOCH 2 CH 2 H 2 NCOCH
2

CH 3 CH 3

CH 2 CONH

2

corin nucleus
H 2 NCOCH O

H 3C H 3C H N
2

N CN Co

CH 2 CH 2 CONH N

2

cobalt coordinated
N CH 3 CH 3 CH 2 CH 2 CONH

H 2C CH 3 CH 3

2

H

N

H 3C O

O P O O OH N CH 3

benzylimidazole
N CH 3

HO VITAMIN B
12

Vitamin B12
? biochemical functions (mediated by coenzymes)
? mutase reaction (rearrangement reaction
– methylmalonyl CoA to succinyl CoA (lipid metabolism)

? methylation reactions
– uracil to thymine – homocysteine to methionine – aminoethanol to choline

? activation of amino acids for protein synthesis ? ribonucleotides to deoxyribonucleotides for DNA synthesis in certain bacteria

Causes of B12 deficiency
? Pernicious anemia (autoimmune gastritis against parietal cells - loss of intrinsic factor) ? rarely due dietary deficiency ? N2O/oral contaceptive drugs ? intestinal parasite ? gastrectomy ? chronic gastritis ? Schilling test

Manifestation of B12 deficiency
? macrocytic megaloblastic anemia
? megaloblasts are abnormal erythroid precursors in bone marrow (most cells die in the bone marrow) ? reticulocyte index is low ? hyperchromic macrocytes appear in blood ? anemia reflects impaired DNA synthesis ? other cells may be involved (leukopenia, thrombocytopenia

? spinal cord degeneration (irreversible)
? ? ? ? swelling, demyelination, cell death neurological disease results from deficient methylmalonyl-CoA mutase this cannot be treated with folic acid!!

Treatment of B12 deficiency
? use IM cyanocobalamin or hydroxocobalamin ? administer daily for 2 - 3 weeks, then every 2 - 4 weeks for life ? monitor reticulocytosis early to assure treatment is working (reticulocyte count should go up) ? monitor potassium levels to ensure hypokalemia does not occur due to excessive RBC synthesis

The fat soluble vitamins

Fat soluble vitamins
? Vitamins A, D, K and E are the fatsoluble vitamins ? excessive use of vitamins A and K can lead to toxicities ? fat soluble vitamin tend to be stored in fatty tissues of the body and in the liver

Vitamin A
? Exists in 3 forms:
? all trans-retinol ? long chain fatty acyl ester of retinol (main storage form) ? retinal (the active form in the retina)

? retinoic acid is also considered to be physiologically active ? provitamin A or carotene can be converted to retinol in vivo ? recommended intakes are expressed in retinol equivalents (RE) 1 RE = 1 mcg of retinol = 6 mcg of βcarotene = 12 mcg other carotenes

? older usage expressed activity in USP units or International units (IU). These were based on biological activity in the vitamin a-deficient rat (1 IU = 0.3 mcg of retinol)

Vitamin A contains 5 conjugated double bonds which are key to some biological actions Isolated in impure form by McCollum in 1915

CH 3 H 3C CH 3

CH 3 CH 2OH

CH 3
RDA: 0.7 mg

VITAMIN A (RETINOL)

Vitamin A

? Diseases of deficiency:
– Nigh blindness and xerophthalmia (dry eye) – Skin disorders – Lack of growth

? Hypervitaminosis:
– A serious potential problem (CNS disorders; birth defects)

H3C H3C CH3 CH3 CH3

H3C CH3 CH3 CH3

CH3

β-carotene

liver O2

H3C

CH3

CH3

CH3

H3C

CH3

CH3

CH3

H

O OH CH3 CH3

retinol (from diet)

retinal (active form in vision)

H3C

CH3

CH3

CH3

H3C

CH3

CH3

CH3 COOH

O

CH3

vitamin A acetate (R = CH3) vitamin A palmitate (R = C16H33 R
O

CH3

retinoic acid ("hormonally-active form")

Vision and the role of vitamin A
? photoreception is the function of 2 specialized cell types: rods and cones ? both types of cells contain a photosensitive compound called opsin
– in rod cells opsin is called scotopsin and the receptor is called rhodopsin or visual purple – rhodopsin is a serpentine receptor imbedded in the membrane of the rod cell; it is a complex between scotopsin and 11-cis retinal

? intracellularly, rhodopsin is coupled to a G-protein called transducin ? when rhodopsin is exposed to light, it is bleached releasing the 11-cis-retinal from opsin

Vision and the role of vitamin A
? absorption of photons by 11-cis-retinal triggers the conversion to all-trans-retinal (one important conformational intermediate is metarhodopsin II); also there is a change in conformation of the photoreceptor ? these transformations activate a phosphodiesterase (which hydrolyzes c-GMP to GMP) ? c-GMP is necessary to maintain the Na+ channels in the rods in the open conformation ? with a decrease in c-GMP, there occurs a closure of the Na+ channels, which leads to hyperpolarization of the rod cells with concomittant propagation of nerve impulses to the brain

CH 3 H 3C CH 3

11-cis

H O CH 3 H 3C N Schiff's base H RHODOPSIN (11-cis retinal + opsin) lysine chain of opsin 1. light 2. isomerization of retinal 3. change in shape of rhodopsin O CH 3 H 3C CH 3 N H H 3C 11-trans retinal N H CH 3 H N N

H N

signal transduction

nerve impulse

Vitamin A toxicity
? vitamin A is higly toxic when taken in large amounts either acutely or chronically ? may occur with 200 mg (666,000 IU) in adults or half this amount in children ? signs include headache, nausea and vomiting, increased cerebrospinal fluid pressure, blurred vision and bulging of the fontanelle in infants

Vitamin D
? There are 2 major precursor forms:
? 7-dehydrocholesterol ? ergosterol

? UV irradiation affords cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) ? Discovery:
? 1890 – sunlight prevents rickets ? 1924 – Steanbock and Hess found that irradiating certain foods produced vitamin D2 ? 1970 – hormonally active form of vitamin D discovered

Vitamin D
? RDA – 20 ?g (required in minute amounts) ? disease of deficiency: rickets
? Malformation of bones – due to improper bone mineralization

? Hypervitaminosis
? Toxic dose only 10X higher than the RDA ? Causes hypercalcemia – can lead to cardiac arrest

? vitamin D is not a vitamin (or a cofactor) – it is a steroid hormone

Chemical name

Abbreviation

Generic name

Vitamin D2

D2

ergocalciferol

Vitamin D3

D3

Cholecalciferol

25hydroxyvitamin D3 1,25-dihydroxy vitamin D3

25(OH)D 3

calciferol

1,25-(OH)3

Calcitriol

24,25-dihydroxy 24,25(OH)2D3 vitamin D3

Secalcifediol

OH

HO 7-DEHYDROCHOLESTEROL

CH 3

PRE-D

3

D 3 (CHOLECALCIFEROL) CH 2

HO

Vit. D biological functions
? Calcium homeostasis – it is critical for the body to maintain the proper calcium level in the blood stream
– Intestinal calcium absorption: acts as a signal to tell intestinal cells to take up more calcium from the gut – Bone calcium mobilization
? Signals osteoclast (bone cells) to release calcium into the blood stream in response to low calcium levels

Vitamin E
? alpha (E1), beta (E2) and gamma(E3) tocopherol ? sources: plant oils (corn, peanut, wheat germ), green leafy vegetables, meat, eggs ? value resides in the antioxidant properties of vitamin E (may prevent the formation of peroxides)

ALPHA TOCOPHEROL

CH3 CH3 H3C O CH3 HO CH3 ALPHA TOCOPHEROL CH3 CH3 CH3

Found in a variey of different sources (primarily vegetable fats)

Vitamin E
? Estimated requirements: 5 mg/day + 0.6 mg/day of unsaturated fat ? Biological function – antioxidant for fatty acids
– Acts like vitamin C; prevents lipid peroxidation and/or damage to cells by lipid hydroperoxides

Prescriptions for Vitamin E
? hemolytic anemia in premature infants, unresponsive to B12, Fe and folic acid ? macrocytic megaloblastic anemia seen in children with severe protein-calorie malnutrition

Vitamin K
? the koagulation vitamin ? exists in 2 forms:
– plant origin: phylloquinone or vit K1 – bacterial origin: menaquinones or vit K2

? also certain synthetic quinones have vitamin K activity
– menadione (vitamin K3) – menadiol sodium phosphate (vitamin K4)

O CH3 CH3 O CH3 3 CH3

PHYTONADIONE (VITAMIN K 1; PHYLLOQUINONE)

O CH 3 CH 3 O CH 3 n = 1 -12 CH 3

MENAQUINONE (VITAMIN K 2 SERIES)

O CH3

O MENADIONE (VITAMIN K3)


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